J Hum Genet. 2025 Sep 26. doi: 10.1038/s10038-025-01409-y. Online ahead of print.
ABSTRACT
Non-invasive prenatal testing (NIPT) enables the screening of fetal chromosomal abnormalities by analyzing cell-free DNA (cfDNA) in maternal blood. Recent technological advancements have expanded its applications to the detection of copy number variations (CNVs). However, the clinical utility of CNV detection remains unclear. We aimed to investigate the association between fetal CNVs detected by genome-wide NIPT and perinatal outcomes in a large cohort in Japan. This retrospective cohort study included 46,082 patients who underwent NIPT at certified facilities in Japan between January 2015 and September 2021. Genome-wide NIPT was performed using massively parallel sequencing to detect fetal CNVs exceeding 7 Mb. Despite their small size, well-characterized microdeletions, such as 22q11.2 were included. From 46,082 patients with NIPT results, 30,373 cases with known birth outcomes were extracted, and cases with fetal CNV were included in the analysis. Fetal CNVs were detected in 66 patients (0.2%). Adverse outcomes, including miscarriage, growth restriction, and structural abnormalities, were observed in 14 of the 66 cases (21.2%). Pathogenic CNVs were frequently detected even in the 52 cases (78.8%) with favorable outcomes. Genome-wide NIPT may assist in the diagnosis of cases with structural abnormalities when combined with confirmatory testing. Our findings demonstrate that pathogenic CNVs are also detected in a substantial number of structurally normal fetuses with favorable short-term outcomes. This discordance presents a significant challenge for prenatal counseling. The clinical significance of the findings should be clarified through confirmatory testing of CNV cases and the accumulation of data from long-term follow-up studies.
PMID:40999196 | DOI:10.1038/s10038-025-01409-y
